Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA327285 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Thyroid transcription factor-1 (TTF-1), also known as NKX2-1, plays a role as a lineage-survival oncogene in lung adenocarcinoma with double-edged sword characteristics. Although previous studies steadily accumulated evidence for roles of TTF-1 in the transcriptional regulation of protein-coding genes, very little is known about its regulatory relationship with miRNAs. In this study, we have identified miR-532-5p as a novel transcriptional target of TTF-1 by an integrative approach, which was designed to extract maximal information from expression profiles of both patient tumors in vivo and TTF-1-inducible cell lines in vitro. Consequently, we have found that miR-532-5p is directly regulated by TTF-1 through its binding to a genomic region 8 kb upstream of miR-532-5p, which appeared to impose transcriptional regulation independent of that of CLCN5, a protein-coding gene harboring miR-532-5p in its intron 3. Further, we have also identified KRAS and MKL2 as novel direct targets of miR-532-5p. Introduction of miR-532-5p mimics markedly induced apoptosis in KRAS-mutant as well as KRAS wildtype lung adenocarcinoma cell lines. Interestingly, miR-532-5p affected the MEK-ERK pathway signaling specifically in cell lines sensitive to siKRAS treatment, while the miR-532-5p-mediated effects were clearly phenocopied by repressing expression or inhibiting function of MKL2 regardless of KRAS mutation status. In summary, our findings demonstrate that miR-532-5p is as novel transcriptional target of TTF-1 and plays a tumor suppressive role by targeting KRAS and MKL2 in lung adenocarcinoma. Novel therapeutic strategies using miR-532-5p or an MKL2 inhibitor may prove effective against this hard-to-cure cancer irrespective of the dependence on KRAS-mediated signaling.
2017-06-21 | GSE83838 | GEO
Project description:Thyroid transcription factor-1 (TTF-1), also known as NKX2-1, plays a role as a lineage-survival oncogene in lung adenocarcinoma with double-edged sword characteristics. Although previous studies steadily accumulated evidence for roles of TTF-1 in the transcriptional regulation of protein-coding genes, very little is known about its regulatory relationship with miRNAs. In this study, we have identified miR-532-5p as a novel transcriptional target of TTF-1 by an integrative approach, which was designed to extract maximal information from expression profiles of both patient tumors in vivo and TTF-1-inducible cell lines in vitro. Consequently, we have found that miR-532-5p is directly regulated by TTF-1 through its binding to a genomic region 8 kb upstream of miR-532-5p, which appeared to impose transcriptional regulation independent of that of CLCN5, a protein-coding gene harboring miR-532-5p in its intron 3. Further, we have also identified KRAS and MKL2 as novel direct targets of miR-532-5p. Introduction of miR-532-5p mimics markedly induced apoptosis in KRAS-mutant as well as KRAS wildtype lung adenocarcinoma cell lines. Interestingly, miR-532-5p affected the MEK-ERK pathway signaling specifically in cell lines sensitive to siKRAS treatment, while the miR-532-5p-mediated effects were clearly phenocopied by repressing expression or inhibiting function of MKL2 regardless of KRAS mutation status. In summary, our findings demonstrate that miR-532-5p is as novel transcriptional target of TTF-1 and plays a tumor suppressive role by targeting KRAS and MKL2 in lung adenocarcinoma. Novel therapeutic strategies using miR-532-5p or an MKL2 inhibitor may prove effective against this hard-to-cure cancer irrespective of the dependence on KRAS-mediated signaling.
2017-06-21 | GSE83837 | GEO
Project description:Thyroid transcription factor-1 (TTF-1), also known as NKX2-1, plays a role as a lineage-survival oncogene in lung adenocarcinoma with double-edged sword characteristics. Although previous studies steadily accumulated evidence for roles of TTF-1 in the transcriptional regulation of protein-coding genes, very little is known about its regulatory relationship with miRNAs. In this study, we have identified miR-532-5p as a novel transcriptional target of TTF-1 by an integrative approach, which was designed to extract maximal information from expression profiles of both patient tumors in vivo and TTF-1-inducible cell lines in vitro. Consequently, we have found that miR-532-5p is directly regulated by TTF-1 through its binding to a genomic region 8 kb upstream of miR-532-5p, which appeared to impose transcriptional regulation independent of that of CLCN5, a protein-coding gene harboring miR-532-5p in its intron 3. Further, we have also identified KRAS and MKL2 as novel direct targets of miR-532-5p. Introduction of miR-532-5p mimics markedly induced apoptosis in KRAS-mutant as well as KRAS wildtype lung adenocarcinoma cell lines. Interestingly, miR-532-5p affected the MEK-ERK pathway signaling specifically in cell lines sensitive to siKRAS treatment, while the miR-532-5p-mediated effects were clearly phenocopied by repressing expression or inhibiting function of MKL2 regardless of KRAS mutation status. In summary, our findings demonstrate that miR-532-5p is as novel transcriptional target of TTF-1 and plays a tumor suppressive role by targeting KRAS and MKL2 in lung adenocarcinoma. Novel therapeutic strategies using miR-532-5p or an MKL2 inhibitor may prove effective against this hard-to-cure cancer irrespective of the dependence on KRAS-mediated signaling.
2017-06-21 | GSE83836 | GEO
Project description:TTF-1-regulated miR-532-5p targets KRAS and MKL2 oncogenes and induces apoptosis in lung adenocarcinoma
| PRJNA327170 | ENA
Project description:TTF-1-regulated miR-532-5p targets KRAS and MKL2 oncogenes and induces apoptosis in lung adenocarcinoma [cell line]
| PRJNA327284 | ENA
Project description:TTF-1-regulated miR-532-5p targets KRAS and MKL2 oncogenes and induces apoptosis in lung adenocarcinoma [rt-pcr]
| PRJNA327171 | ENA
Project description:Adenocarcinoma is the most common histologic subtype of lung cancer, which is the leading cause of cancer death. We and others previously identified TTF-1, a lineage-specific transcription factor required for branching morphogenesis and physiological lung functions, as a lineage-survival oncogene in lung adenocarcinoma. However, how TTF-1 mediates survival signals remains elusive. Here we show that TTF-1 induces receptor tyrosine kinase-like orphan receptor 1 (ROR1), which in turn mediates TTF-1 survival signaling in lung adenocarcinoma. Inhibition of ROR1 impaired prosurvival signaling through the PI3K-AKT pathway and induced nuclear accumulation of FOXO1. These were found to be imposed, at least in part, through PTEN inactivation via c-Src, while ROR1 was shown to physically interact with and phosphorylate c-Src. ROR1 inhibition also elicited marked p38 activation, provoking ill-balance between prosurvival and proapoptotic signaling, and consequential “oncogenic shock.” In addition, we found that ROR1 is crucially involved in EGFR- and MET-mediated prosurvival signaling. ROR1 knockdown effectively induced apoptosis in lung adenocarcinoma cell lines with acquired EGFR TKI resistance conferred by a secondary T790M EGFR mutation, or HGF-elicited MET signaling and resultant switching of the addicted receptor tyrosine kinases (RTKs). Taken together, our findings indicate that ROR1 RTK is a very promising molecular target for development of a novel therapeutic means to treat this hard-to-cure cancer. Dye-swap experiment, vector control vs. stable TTF-1 transfectant of HPL1D, immortalized human peripheral lung epithelial cell line.
2011-12-31 | E-GEOD-25830 | biostudies-arrayexpress
Project description:Adenocarcinoma is the most common histologic subtype of lung cancer, which is the leading cause of cancer death. We and others previously identified TTF-1, a lineage-specific transcription factor required for branching morphogenesis and physiological lung functions, as a lineage-survival oncogene in lung adenocarcinoma. However, how TTF-1 mediates survival signals remains elusive. Here we show that TTF-1 induces receptor tyrosine kinase-like orphan receptor 1 (ROR1), which in turn mediates TTF-1 survival signaling in lung adenocarcinoma. Inhibition of ROR1 impaired prosurvival signaling through the PI3K-AKT pathway and induced nuclear accumulation of FOXO1. These were found to be imposed, at least in part, through PTEN inactivation via c-Src, while ROR1 was shown to physically interact with and phosphorylate c-Src. ROR1 inhibition also elicited marked p38 activation, provoking ill-balance between prosurvival and proapoptotic signaling, and consequential “oncogenic shock.” In addition, we found that ROR1 is crucially involved in EGFR- and MET-mediated prosurvival signaling. ROR1 knockdown effectively induced apoptosis in lung adenocarcinoma cell lines with acquired EGFR TKI resistance conferred by a secondary T790M EGFR mutation, or HGF-elicited MET signaling and resultant switching of the addicted receptor tyrosine kinases (RTKs). Taken together, our findings indicate that ROR1 RTK is a very promising molecular target for development of a novel therapeutic means to treat this hard-to-cure cancer.
2011-12-31 | GSE25830 | GEO
Project description:Aberrant activation of RAS oncogenes is a prevalent event in lung adenocarcinoma, with somatic mutation of KRAS occurring in ~30% of tumors. Recently, we identified somatic mutation of the RAS-family GTPase RIT1 in lung adenocarcinoma, but relatively little is known about the biological pathways regulated by RIT1 and how these relate to the oncogenic KRAS network. Here we present (quantitative proteomic and) transcriptomic profiles from KRAS-mutant and RIT1-mutant isogenic lung epithelial cells and globally characterize the signaling networks regulated by each oncogene.
2020-03-06 | GSE146479 | GEO
Project description:Based on the previous eVIP study (Cancer Cell, 2016), we profiled the transcriptomes of lung adenocarcinoma cell lines expressing oncogenic KRAS and TP53 to compare methods and investigate the effects of these oncogenes on the cells' whole transcriptomes.
2021-10-01 | GSE183670 | GEO